Management of patients with advanced prostate cancer: recommendations of the St Gallen Advanced Prostate Cancer Consensus Conference (APCCC) 2015.

The first St Gallen Advanced Prostate Cancer Consensus Conference (APCCC) Expert Panel identified and reviewed the available evidence for the ten most important areas of controversy in advanced prostate cancer (APC) management. The successful registration of several drugs for castration-resistant prostate cancer and the recent studies of chemo-hormonal therapy in men with castration-naïve prostate cancer have led to considerable uncertainty as to the best treatment choices, sequence of treatment options and appropriate patient selection. Management recommendations based on expert opinion, and not based on a critical review of the available evidence, are presented. The various recommendations carried differing degrees of support, as reflected in the wording of the article text and in the detailed voting results recorded in supplementary Material, available at Annals of Oncology online. Detailed decisions on treatment as always will involve consideration of disease extent and location, prior treatments, host factors, patient preferences as well as logistical and economic constraints. Inclusion of men with APC in clinical trials should be encouraged.

Muscle invasive bladder cancer: closing the gap between practice and evidence.

Bladder cancer is the fourth most common cancer in the United States, and will lead to an estimated 15,580 deaths in 2014. Prompted by physical symptoms and signs, most patients will initially present with clinically localized disease. Once bladder cancer invades beyond the muscularis propria, the likelihood of development of metastatic disease increases substantially. Radical cystectomy is potentially curative for muscle-invasive bladder cancer though approximately 50% of patients will develop metastatic recurrence. Two large randomized studies have demonstrated that the use of neoadjuvant cisplatin-based chemotherapy prior to cystectomy improves survival. However, despite the existing level 1 evidence, this approach has been largely underutilized in practice. In this review, we will focus on this disconnect between efficacy and effectiveness and explore possible solutions in an effort to bridge this existing gap.

Comparative effectiveness of cisplatin-based and carboplatin-based chemotherapy for treatment of advanced urothelial carcinoma.

BACKGROUND: Cisplatin-based chemotherapy is a standard treatment of metastatic urothelial carcinoma (UC), though carboplatin-based chemotherapy is frequently substituted due to improved tolerability. Because comparative effectiveness in clinical outcomes of cisplatin- versus carboplatin-based chemotherapy is lacking, a meta-analysis was carried out. METHODS: PubMed was searched for articles published from 1966 to 2010. Eligible studies included prospective randomized trials evaluating cisplatin- versus carboplatin-based regimens in patients with metastatic UC. Individual patient data were not available and survival data were inconsistently reported. Therefore, the analysis focused on overall response (OR) and complete response (CR) rates. The Mantel-Haenszel method was used for combining trials and calculating pooled risk ratios (RRs). RESULTS: A total of 286 patients with metastatic UC from four randomized trials were included. Cisplatin-based chemotherapy was associated with a significantly higher likelihood of achieving a CR [RR = 3.54; 95% confidence interval (CI) 1.48-8.49; P = 0.005] and OR (RR = 1.34; 95% CI 1.04-1.71; P = 0.02). Survival end points could not be adequately assessed due to inconsistent reporting among trials. CONCLUSIONS: Cisplatin-based, as compared with carboplatin-based, chemotherapy significantly increases the likelihood of both OR and CR in patients with metastatic UC. The impact of improved response proportions on survival end points could not be assessed.

Phase I study of the effects of renal impairment on the pharmacokinetics and safety of satraplatin in patients with refractory solid tumors.

BACKGROUND: Satraplatin is an oral platinum analog with demonstrated activity in a range of malignancies. The current study was designed to evaluate the effect of varying degrees of renal impairment on the safety and pharmacokinetics (PKs) of satraplatin. PATIENTS AND METHODS: Patients with advanced solid tumors, refractory to standard therapies, were eligible. The study included four cohorts of patients with varying levels of renal function, and eight patients per cohort: Group 1 (G1) = normal renal function; G2 = mild renal impairment [creatinine clearance (CrCl) 50-80 ml/min]; G3 = moderate impairment (CrCl 30 to <50 ml/min); G4 = severe impairment (CrCl <30 ml/min). Satraplatin was administered orally at 80 mg/m(2)/day on days 1-5 every 35 days. RESULTS: A total of 32 patients were enrolled, 8 patients in each renal function group. Each group tolerated the dose of 80 mg/m(2)/day on days 1-5 every 35 days without the need for dose deescalation. The most common adverse events were fatigue (63%), nausea (56%), diarrhea (53%), anorexia (47%), constipation (38%), vomiting (28%), anemia, dyspnea, and thrombocytopenia (25%). There were no dose-limiting toxic effects in any study group. There was increased exposure to plasma platinum and plasma ultrafiltrate platinum in patients with moderate to severe renal impairment. CONCLUSIONS: Satraplatin PKs was altered in patients with renal impairment. However, a corresponding increase in satraplatin-related toxic effects was not observed.

Efficacy of carboplatin-taxane combinations in the management of castration-resistant prostate cancer: a pooled analysis of seven prospective clinical trials.

BACKGROUND: Docetaxel is associated with prolonged survival in castration-resistant prostate cancer (CRPC). Platinum compounds have modest but distinct single-agent activity. Carboplatin may have greatest potential for benefit when combined with taxanes. We investigated whether there is a subset of patients with CRPC for whom the efficacy of combination taxane-estramustine-carboplatin (TEC) chemotherapy may be greatest. PATIENTS AND METHODS: Individual patient data (n = 310) were obtained from seven trials using TEC chemotherapy. Prostate-specific antigen (PSA) response was defined as > or = 50% post-therapy decline from baseline. Overall survival was defined from baseline to death from any cause. Logistic and Cox regression were used to investigate heterogeneity in outcome to TEC by patient and disease characteristics. Predicted survival probabilities were calculated from the Halabi Cancer and Leukemia Group B (CALGB) nomogram. RESULTS: The pooled PSA response proportion was 69% [95% confidence interval (CI) 56% to 80%]. There was no evidence of differential PSA response by disease characteristics. Established prognostic factors were associated with survival. The pooled 12-month survival estimate of 79% (95% CI 71% to 84%) was higher than the median 59% 12-month nomogram-predicted survival. CONCLUSIONS: TEC chemotherapy has significant clinical activity in CRPC. A randomized, controlled trial evaluating the addition of carboplatin to taxane-based chemotherapy is needed to elucidate the value of carboplatin in CRPC.

Phase II study of sunitinib in men with advanced prostate cancer.

BACKGROUND: This study explored the efficacy and tolerability of sunitinib, an inhibitor of tyrosine kinase receptors, in men with castration-resistant prostate cancer (CRPC). METHODS: Men with no prior chemotherapy (group A) and men with docetaxel (Taxotere)-resistant prostate cancer (group B) were treated with sunitinib. The primary end point was confirmed 50% prostate-specific antigen (PSA) decline. Secondary end points included objective response rate and safety. Serum-soluble biomarkers were measured. RESULTS: Seventeen men were enrolled in each group. One confirmed PSA response was observed in each group, and an additional eight men and seven men had stable PSA at week 12 in groups A and B, respectively. Improvements in imaging were observed in the absence of post-treatment PSA declines. Common adverse effects included fatigue, nausea, diarrhea, myelosuppression and transaminase elevation. Significant changes following sunitinib treatment were observed in serum-soluble biomarkers including soluble vascular endothelial growth factor receptor-2, platelet-derived growth factor aa, placental growth factor and leptin. CONCLUSIONS: Sunitinib monotherapy resulted in few confirmed 50% post-treatment declines in PSA in men with CRPC. Serum markers of angiogenesis confirmed on-target effects of sunitinib. Assessments of radiographic disease status were often discordant with changes in PSA, indicating that alternate end points are important in future trials.

Dynamic change in phosphorylated platelet-derived growth factor receptor in peripheral blood leukocytes following docetaxel therapy predicts progression-free and overall survival in prostate cancer.

In a placebo-controlled randomised study of the platelet-derived growth factor receptor (PDGFR) inhibitor imatinib mesylate and docetaxel in metastatic prostate cancer with bone metastases (n=116), no significant differences in progression-free and overall survival were observed. To evaluate pharmacodynamic correlates of outcomes, we assessed the association of plasma platelet-derived growth factor (PDGF) isoform kinetics and PDGFR inhibition with progression-free and overall survival by individual treatment arm. We found that in the docetaxel-placebo arm alone, the probability of decrease in PDGFR phosphorylation (Pr-Decr-pPDGFR) above 0.5 (vs 30 months (HR 3.1; P=0.04 in log-rank test). By contrast, in the docetaxel plus imatinib arm, the association of Pr-Decr-pPDGFR >0.5 with a rise in plasma PDGF isoform concentrations and inferior survival was not observed. The data suggest that dynamic changes in PDGFR phosphorylation in peripheral blood leukocytes predict docetaxel efficacy. Rising plasma PDGF concentrations may explain and/or mark docetaxel resistance. Validation and mechanistic studies addressing these unexpected findings should anticipate a confounding influence of concurrent PDGFR inhibitor therapy.

Colorimetric heparinase assay for alternative anti-metastatic activity.

Heparanase has been previously associated with the metastatic potential, inflammation, and angiogenesis of tumor cells. Heparanase activity has been detected by means of UV absorption, radiolabeled substrates, electrophoretic migration, and heparan sulfate affinity assays. However, those methods have proven to be somewhat problematic with regards to application to actual biological samples, the accessibility of the immobilized substrates, experimental sensitivity, and the separation of degraded products. Rather than focusing on heparanase activity, then, we have developed a rapid, alternative colorimetric heparinase assay, on the basis of the recent finding that sulfated disaccharides generated from heparin by bacterial heparinase exhibit biological properties comparable to those from heparan sulfate by mammalian heparanase. In this study, the concentrations of porcine heparin and bacterial heparinase I were determined using a Sigma Diagnostics Kit. Morus alba was selected as a candidate through this assay system, and an inhibitor, resveratrol, was purified from its methanol extract. Its anti-metastatic effects on the pulmonary metastasis of murine B16 melanoma cells were also evaluated. Our findings suggest that this assay may prove useful as a diagnostic tool for heparinase inhibition, as an alternative anti-metastatic target.

Inhibition of PDGF-induced phospholipase C activation by herbimycin A.

Herbimycin A, an inhibitor of protein tyrosine kinases, dose-dependently reduced PDGF-induced inositol phosphates (IPt) accumulation without effect on phosphatidylethanol (PEt) formation in PLC-gamma 1-overexpressing NIH 3T3 (NIH 3T3 gamma 1) cells. The compound also reduced tyrosine phosphorylations of some proteins including PLC-gamma 1 in response to PDGF. On the other hand, phorbol 12-myristate 13-acetate (PMA)-induced phospholipase D (PLD) activation was reduced by herbimycin A in the cells, indicating that the pathways for PLD activation by PDGF and PMA are different from each other. Also, these results suggest that PLC-gamma 1 activation is not always an upstream event for PLD activation and that tyrosine phosphorylation of one or more proteins not affected by herbimycin A should be indispensable for PLD activation in PDGF-stimulated NIH 3T3 gamma 1 cells.

Treatment of locally advanced prostate cancer: is chemotherapy the next step?

PURPOSE: Management of locally advanced prostate cancer remains controversial. Various single and combination modality approaches have been advocated, but an accepted standard of care remains undefined. The purpose of this review is to define the current knowledge in managing locally advanced prostate cancer and to propose new treatment approaches based on current knowledge. MATERIALS AND METHODS: A MEDLINE search to detect all relevant articles on the management of locally advanced prostate cancer was performed. A review of the staging, natural history, and prognosis of this disease was also performed. RESULTS: The lack of a clearly defined treatment approach to patients with locally advanced prostate cancer stems from multiple factors, including ambiguities in clinical staging, inadequate knowledge of the natural history of the cancer, and a dearth of comparative randomized trials evaluating efficacy of different therapies. Single modality treatment, including radical prostatectomy (RP) or external-beam radiotherapy alone, is associated with high rates of failure. The use of adjuvant hormonal ablation therapy in combination with external-beam radiotherapy has shown improvement in progression-free and overall survival, although similar improvements have not been clearly demonstrated for surgical patients treated with hormonal therapy. New advances in chemotherapy for hormone-refractory prostate cancer suggest that response rates may be as high as 50% or more, and current trials are evaluating the addition of chemotherapy to hormonal ablation in either surgery or radiation therapy in locally advanced prostate cancer. CONCLUSION: Optimal management of locally advanced prostate cancer remains undefined. Standard treatment options include RP, external-beam radiotherapy, or hormonal ablation therapy, alone or in combination. New approaches being tested include improved methods for delivering radiation or combining hormonal ablation with surgery or radiation. It is possible that other forms of systemic therapy, including chemotherapy, may become important components of multimodality treatment. Clinical trials designed to test this hypothesis are ongoing.

A phase I trial of a recombinant vaccinia virus expressing prostate-specific antigen in advanced prostate cancer.

A recombinant vaccinia virus encoding human prostate-specific antigen (rV-PSA) was administered as three consecutive monthly doses to 33 men with rising PSA levels after radical prostatectomy, radiation therapy, both, or metastatic disease at presentation. Dose levels were 2.65 x 10(6), 2.65 x 10(7), and 2.65 x 10(8) plaque forming units. Ten patients who received the highest dose also received 250 microg/m2 granulocyte-macrophage colony-stimulating factor (GM-CSF) as an immunostimulatory adjunct. No patient experienced any virus-related effects beyond grade I cutaneous toxicity. Pustule formation and/or erythema occurred after the first dose in all 27 men who received > or =2.65 x 10(7) plaque forming units. GM-CSF administration was associated with fevers and myalgias of grade 2 or lower in 9 of 10 patients. PSA levels in 14 of 33 men treated with rV-PSA with or without GM-CSF were stable for at least 6 months after primary immunization. Nine patients remained stable for 11-25 months; six of these remain progression free with stable PSA levels. Immunological studies demonstrated a specific T-cell response to PSA-3, a 9-mer peptide derived from PSA. rV-PSA is safe and can elicit clinical and immune responses, and certain patients remain without evidence of clinical progression for up to 21 months or longer.

Involvement of SH2-SH2-SH3 domain of phospholipase cgamma1 in NF-kappaB signaling.

To directly define the role of phospholipase Cgamma1 (PLCgamma1) in NF-kappaB activation, NF-kappaB promoted luciferase reporter gene plasmid (pNF-kappaB-Luc) was transfected into rat-3Y1 fibroblasts that overexpress whole PLCgamma1 (PLCgamma1-3Y1), src homology domains SH2-SH2-SH3 of PLCgamma1 (SH223-3Y1) and v-src (Src-3Y1). Transient transfection with pNF-kappaB-Luc remarkably increased the luciferase activity in all three transformants compared with normal rat-3Y1 cells. Pretreatment with inhibitors of protein tyrosine kinase reduced this increase in luciferase activity, but U73122 (a PLC inhibitor) did not. While PD98059, an inhibitor of mitogen activated protein kinase (MAPK), significantly reduced the luciferase activity, there was no effect by wortmannin and Ro-31-8220, inhibitors of phosphatidylinositol 3-kinase (PI3K) and protein kinase C (PKC), respectively. This study shows a direct evidence that the SH2-SH2-SH3 region of PLCgamma1 contributes to the NF-kappaB signaling and that MAPK, but not PI3K and PKC, is involved in SH2-SH2-SH3 mediated NF-kappaB activation in these cells.

Docetaxel (Taxotere)-based chemotherapy for hormone-refractory and locally advanced prostate cancer.

Treatment of hormone-refractory prostate cancer (HRPC) historically has shown limited efficacy. However, taxane-based chemotherapy regimens recently have demonstrated more promising results. Several groups have reported significant efficacy and minimal toxicity in patients with hormone-refractory disease receiving estramustine plus docetaxel (Taxotere; Rhône-Poulenc Rorer, Collegeville, PA). Others have demonstrated single-agent activity of platinum compounds in HRPC. Therefore, the combination of estramustine, docetaxel, and carboplatin is currently being tested in two separate trials of HRPC. The first is a Dana-Farber/Partners Cancer Care phase I study of estramustine, carboplatin, and escalating doses of weekly docetaxel. The second study is a Cancer and Leukemia Group B multicenter phase II study evaluating the combination of estramustine, docetaxel, carboplatin, and granulocyte colony-stimulating factor. The promise of taxane-based regimens in the treatment of hormone-refractory disease has led to consideration of treating patients at high risk for developing metastatic disease earlier in their clinical course. At Dana-Farber/ Partners Cancer Care, we are evaluating neoadjuvant weekly docetaxel alone followed by surgery in patients with high-risk localized prostate cancer using pathologic response as the primary end point. Adding carboplatin to the active combination of estramustine and docetaxel may improve the response rate in HRPC. Furthermore, the use of promising chemotherapy agents earlier in high-risk localized disease may improve clinical outcomes in these patients by decreasing their risk for systemic relapse.

Neoadjuvant docetaxel followed by radical prostatectomy in patients with high-risk localized prostate cancer: a preliminary report.

Effective treatment options for high-risk localized prostate cancer are limited. Patients at high risk for recurrence include those with biopsy Gleason scores of 8 to 10, prostate specific antigen (PSA) levels > 20 ng/mL, and clinical stage T3 disease. Docetaxel chemotherapy is active in hormone-refractory prostate cancer, either combined with estramustine or used as a single agent. To determine if systemic therapy can improve the outcome of radical prostatectomy in men with high-risk localized prostate cancer, we are undertaking a pilot phase II clinical trial of weekly docetaxel at 36 mg/m(2) for up to 6 months, followed by surgery. Patients are monitored with weekly visits, monthly digital rectal examinations, PSA measurement, and testosterone tests, and endorectal magnetic resonance imaging done at baseline, after two cycles, and again after six cycles. To date, 15 patients have been enrolled, and 70 cycles of chemotherapy have been administered. Toxicity has been mostly grade 1 in intensity, and fatigue has been the most common grade 2 toxicity reported. The primary endpoint of the trial is measurement of pathologic complete response rate, for which data are not yet available. Recruitment to the trial is ongoing.

Mutagenesis of the glucoamylase signal peptide of Saccharomyces diastaticus and functional analysis in Saccharomyces cerevisiae.

To improve the efficiency of the glucoamylase signal peptide (GSP) of Saccharomyces diastaticus for the secretion of foreign proteins, hybrid plasmids containing one of four types of GSP mutant (m1, Pro(-18)-->Leu(-18); m2, Tyr(-13)-->Leu(-13); m3, Ser(-9)-->Leu(-9); m4, Asn(-5)-->Pro(-5)) were constructed and evaluated in Saccharomyces cerevisiae using Bacillus endo-1,4-beta-D-glucanase (CMCase) as a reporter gene. CMCase secretion by m1, m2 and m3 GSP mutants was increased, likely resulting from a higher probability of the modified GSP to assume an alpha-helical structure. Especially in the case of m3, the substitution of Leu for a polar residue, Ser(-9), in the hydrophobic region resulted in approximately a twofold increase in extracellular CMCase activity. In mutant 4, which disrupts the alpha-helix of GSP, CMCase was less efficiently secreted.

Analysis of the correlation between endorectal MRI response to neoadjuvant chemotherapy and biochemical recurrence in patients with high-risk localized prostate cancer.

BACKGROUND: Intermediate end points are desirable to expedite the integration of neoadjuvant systemic therapy into the treatment strategy for high-risk localized prostate cancer. Endorectal magnetic resonance imaging at 1.5 Tesla (1.5T erMRI) response has been utilized as an end point in neoadjuvant trials but has not been correlated with clinical outcomes. METHODS: Data were pooled from two trials exploring neoadjuvant chemotherapy in high-risk localized prostate cancer. Trial 1 explored docetaxel for 6 months and Trial 2 explored docetaxel plus bevacizumab for 4.5 months, both before radical prostatectomy. erMRI was done at baseline and end of chemotherapy. 1.5T erMRI response, based upon T2W sequences, was recorded. Multivariable Cox regression was undertaken to evaluate the association between clinical parameters and biochemical recurrence. RESULTS: There were 53 evaluable patients in the combined analysis: 20 (33%) achieved a PSA response, 16 (27%) achieved an erMRI partial response and 24 (40%) achieved an erMRI minor response. Median follow-up was 4.2 years, and 33 of 53 evaluable (62%) patients developed biochemical recurrence. On multivariable analysis, PSA response did not correlate with biochemical recurrence (hazard ratio=0.58, 95% confidence interval (CI) 0.25-1.33) and paradoxically erMRI response was associated with a significantly shorter time to biochemical recurrence (hazard ratio=2.47, 95% CI 1.00-6.13). CONCLUSIONS: Response by 1.5T erMRI does not correlate with a decreased likelihood of biochemical recurrence in patients with high-risk localized prostate cancer treated with neoadjuvant docetaxel and may be associated with inferior outcomes. These data do not support the use of 1.5T erMRI response as a primary end point in neoadjuvant chemotherapy trials.